Abstract
Thyroid hormone (triiodothyronine, T(3)) is known to activate transcription by binding heterodimers of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs). RXR-TRs bind to T(3) response elements (TREs) composed of direct repeats of the sequence AGGTCA spaced by four nucleotides (DR-4). In other TREs, however, the half-sites can be arranged as inverted palindromes and palindromes (Pal). Here we show that TR homodimers and monomers activate transcription from representative TREs with alternate half-site placements. TR beta activates transcription more efficiently than TR alpha at an inverted palindrome (F2), and this correlates with preferential TR beta homodimer formation at F2 in vitro. Furthermore, reconstruction of TR transcription complexes in yeast indicates that TR beta homodimers are active at F2, whereas RXR-TRs are active at DR-4 and Pal. Finally, analysis of TR beta mutations that block homodimer and/or heterodimer formation reveal TRE-selective requirements for these surfaces in mammalian cells, which suggest that TR beta homodimers are active at F2, RXR-TRs at DR-4, and TR monomers at Pal. TR beta requires higher levels of hormone for activation at F2 than other TREs, and this differential effect is abolished by a dimer surface mutation suggesting that it is related to composition of the TR.TRE complex. We propose that interactions of particular TR oligomers with different elements play unappreciated roles in TRE-selective actions of liganded TRs in vivo.
Highlights
Thyroid hormone receptors (TR␣5 and TR) modulate gene expression by binding to thyroid hormone response elements (TREs) in target gene promoters [1,2,3,4,5]
The fact that TR homodimers dissociate rapidly from cognate TREs and T3 suppresses homodimer formation on DNA has been taken as an argument against a role for this species in T3 activation [1], other studies reveal that TR-TR1⁄7DNA complexes are stabilized by coactivators [32] and that T3 response at IP-6 elements is often independent of coexpressed retinoid X receptor (RXR) in transfections [9, 33]
The findings reported in this study indicate that RXR-TRs are not the only species of TR that is capable of transducing T3 signals in eukaryotic cells; homodimers and monomers play a role
Summary
Thyroid hormone receptors (TR␣5 and TR) modulate gene expression by binding to thyroid hormone response elements (TREs) in target gene promoters [1,2,3,4,5]. The fact that different oligomeric forms of TR bind to DNA and exhibit clear preferences for different TREs raises the possibility that the nature of the response element could influence TR action and T3 response by recruitment of distinct TR transcription complexes with unique activities. The fact that TR homodimers dissociate rapidly from cognate TREs and T3 suppresses homodimer formation on DNA has been taken as an argument against a role for this species in T3 activation [1], other studies reveal that TR-TR1⁄7DNA complexes are stabilized by coactivators [32] and that T3 response at IP-6 elements is often independent of coexpressed RXR in transfections [9, 33]. There are several indications that alternate TR oligomers contribute to T3 induction
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